Psychosocial stress is a precipitating factor in the development of anxiety illnesses and clinical depression, and in the inhibition of positive social behaviors. While psychosocial stress results from a number of situations, there is a strong correlation between socio-economic level and the occurrence of depression and other mental illnesses. Moreover, women are more likely than men to suffer from psychopathology. Because estradiol (E2) has been shown to improve affect and increase motivational behavior, a disruption in E2 action may be important for these stress-induced psychopathologies. However, the importance of E2 on emotion is unclear because hypoestrogenism does not uniformly produce mood disorders in women nor does elevated E2 unequivocally improve affect. We hypothesize that E2's ability to positively affect emotional and social behavior is compromised in individuals experiencing chronic unpredictable psychosocial stress, and that this factor accounts for much of the variability in the effects of E2 on emotion. Understanding how persistent psychosocial stress disrupts E2 is difficult in women. However, animal species which live in a stratified society wherein subordinate females exhibit both stress-induced dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and reduced behavioral sensitivity to E2, provide an ethologically valid model with which to study this question. In these studies we will test the hypothesis that social subordination produces a physiological state that blunts E2's beneficial effect on motivation and anxiety and hence necessitates higher levels of E2 to induce sexual and affiliative behaviors. In addition, we will employ highly selective estrogen receptor (ER)-a and ER-a agonists to determine how psychosocial stress disrupts specific aspects of ER function. Lastly, because E2 interacts extensively with the serotonergic (5HT) system to regulate emotion, we will test the hypothesis that subordinate individuals with a specific polymorphism in the promoter region of the gene encoding the 5HT reuptake transporter (SERT), are more vulnerable to this disruptive effect of psychosocial stress even when co-treated with E2; show less 5HT binding activity in specific brain areas associated with emotionality; and are less behaviorally responsive to treatment with 5HT reuptake inhibitors. These studies will quantify social and emotional behaviors; will use a range of hormone replacement strategies and neuroendocrine assessments of the 5HT and LHPA axis; and will employ neuroimaging to quantify 5HT activity in the brain. Results from this series of studies will be particularly pertinent to development of psychopathology in women living in stressful social environments. PUBLIC HEALTH RELEVANCE: Understanding how chronic psychosocial stress disrupts the ability of the gonadal hormone estradiol to positively influence emotion and socially motivated behaviors will provide a more thorough understanding of how psychopathologies emerge in women. Furthermore, these studies will show how a specific genetic polymorphism may further diminish the positive behavioral efficacy of estradiol. These studies will characterize mechanisms that may lead to the development of therapeutic interventions to prevent or minimize the adverse consequences of psychosocial stress on female emotional health.